Evaluation and treatment of hypernatremia: a practical guide for physicians

Hypernatremia (serum sodium concentration >145 mEq/L) is a common electrolyte disorder with increased morbidity and mortality especially in the elderly and critically ill patients. The review presents the main pathogenetic mechanisms of hypernatremia, provides specific directions for the evaluation of patients with increased sodium levels and describes a detailed algorithm for the proper correction of hypernatremia. Furthermore, two representative cases of hypovolemic and hypervolemic hypernatremia are presented along with practical clues for their proper evaluation and treatment. Accurate diagnosis and appropriate treatment is crucial since undercorrection or overcorrection of hypernatremia are both associated with poor patients’ prognosis.     

Central pontine myelinolysis

Central pontine myelinolysis (CPM), a neurologic disorder caused most frequently by rapid correction of hyponatremia, is characterized by demyelination that affects the central portion of the base of the pons. There are no inflammatory changes, and blood vessels are normal. Clinical features usually reflect damage to the descending motor tracts and include spastic tetraparesis, pseudobulbar paralysis, and the locked-in syndrome. Magnetic resonance imaging of the brain, the imaging procedure of choice, shows an area of prolonged T1 and T2 relaxation in the central pons, which may have a characteristic shape. Recovery varies, ranging from no improvement to substantial improvement. To avoid CPM, correction of serum sodium in patients with hyponatremia should not exceed 12 mEq/24 h. We describe a case of CPM in a hyponatremic patient who presented with a cerebellar syndrome with no pyramidal tract involvement and in whom the rate of correction of serum sodium was within the recommended limits.     

蛛网膜下腔出血时血浆心钠素与低钠血症的关系

目的　研究蛛网膜下腔出血 (SAH)后血浆心钠素 (ANP)的水平变化及其与SAH后低钠发生的相关性。方法　采用放射免疫分析技术和离子选择性电极法检测 2 6例SAH患者不同病程的血浆ANP水平和血清钠水平。根据血清钠水平将 2 6例SAH患者分为SAH低钠组和SAH正常钠组 ,与健康对照组的血浆ANP水平进行比较。结果　SAH低钠组发病后 0～ 3d ,7～ 9d ,14～ 16d的血浆ANP水平均显著高于健康对照组 (P <0 0 1) ,且发病 7～ 9d ,14～ 16d的血浆ANP水平高于SAH正常钠组 (P <0 0 1) ;SAH低钠组血浆ANP水平与血清钠之间呈显著负相关。结论　血浆ANP参与SAH后低钠血症的发生 ;临床上对于SAH后血浆ANP水平显著高值的患者 ,需注意低钠的发生和加重可能     

Disorders of water imbalance

Disorders of water imbalance manifest as hyponatremia and hypernatremia. To diagnose these disorders, emergency physicians must maintain a high index of suspicion, especially in the high-risk patient, because clinical presentations may be nonspecific. With severe water imbalance, inappropriate fluid resuscitation in the emergency department may have devastating neurological consequences. The rate of serum sodium concentration correction should be monitored closely to avoid osmotic demyelination syndrome in hyponatremic patients and cerebral edema in hypernatremic patients.     

Association of intranasal desmopressin therapy with overcorrection of severe hyponatremia: A retrospective,propensity score-based,single-center cohort study

PurposeSevere hyponatremia, defined as serum sodium concentration ([sNa]) ≤ 120 mEq/L, requires aggressive treatment to prevent potentially fatal cerebral edema, seizures, and other sequelae, but overcorrection can also result in life-threatening cerebral hemorrhage and demyelination. We compared the safety and efficacy of nasal desmopressin to conventional management for the prevention of [sNa] overcorrection.Material and methodsThis retrospective analysis compared 47 patients treated with desmopressin to 17 patients treated conventionally at a university hospital ICU in Japan between 2013 and 2018 using propensity score-based approaches. The primary outcome was safe [sNa] correction, defined as a ≤ 8 mEq/L difference between baseline and follow-up [sNa] at any time within 24 h of diagnosis.ResultsThe 24-h safe correction rate was significantly greater in the desmopressin group than the conventional treatment group (68% [32/47] vs. 41% [7/17], P = 0.039), and dose–response analysis indicated a positive association between cumulative 24-h desmopressin dose and safe correction at 24 h (P = 0.003). Few overcorrections precluded reliable assessment at 48 h. Exacerbation of hyponatremia was comparable in the two treatment groups.ConclusionsIntranasal desmopressin therapy increased the safe correction of severe hyponatremia. Large prospective trials are warranted to confirm this result.     

Hyponatremia in critical care patients: Frequency,outcome, characteristics,and treatment with the vasopressin V2-receptor antagonist tolvaptan

Hyponatremia is a common problem in critical care patients and is associated with increased duration of hospital stay and increased morbidity and mortality. The prevalence of hyponatremia in the intensive care unit (ICU) has been reported to be as high as 30% to 40%. Recent studies have found hyponatremia at ICU admission in up to 14% of patients in unselected groups; patients with hyponatremia were at elevated risk of mortality vs normonatremic patients. Most cases in the ICU are euvolemic or hypervolemic hyponatremia, with the syndrome of inappropriate secretion of antidiuretic hormone being a predominant cause. The oral selective vasopressin V₂-receptor antagonist tolvaptan is effective in treating euvolemic and hypervolemic hyponatremia and may be useful in the management of hyponatremic critical care patients. Tolvaptan treatment increases serum sodium via aquaresis—ie, increased electrolyte-free water excretion—and thus presents an advantage in patients with syndrome of inappropriate secretion of antidiuretic hormone or other euvolemic states or hypervolemic hyponatremia. This article provides a review of hyponatremia and of the potential use of tolvaptan in critical care settings. Case reports provide examples of tolvaptan use in correcting severe hyponatremia and associated abnormal mental status and in resolving hyponatremia prior to surgery.     

Hyponatremia, heart failure, and the role of tolvaptan

Hyponatremia-usually defined by serum sodium < 135 mEq/L-is common in heart failure (HF); it remains unclear whether it worsens HF or is merely a marker of more severe disease. Hyponatremia may develop from causes besides HF and symptoms may be mistakenly attributed to HF. Hyponatremia correction may be required for optimal HF management in some cases, and it can prevent neurologic complications. Symptoms, volume status, and onset timing determine treatment, which should correct serum sodium in a controlled manner. Arginine vasopressin is elevated in hypervolemic/euvolemic hyponatremia, favoring water reabsorption despite low serum osmolality. The oral selective V(2)-receptor antagonist tolvaptan blocks arginine vasopressin effects in the renal collecting ducts, promoting aquaresis without increasing sodium/potassium excretion. In clinical trials, tolvaptan significantly increased serum sodium in patients with euvolemic/hypervolemic hyponatremia, including HF. When added to conventional HF treatment, tolvaptan produced early symptomatic benefit, without long-term improvement in an HF population consisting primarily of normonatremic patients. Tolvaptan is approved for treatment of clinically significant hypervolemic/euvolemic hyponatremia (serum sodium < 125 mEq/L or less marked symptomatic hyponatremia that has resisted correction with fluid restriction), but not HF without hyponatremia.     

Exertional heat illness and hyponatremia in hikers.

We compared clinical presentation and course of exercise-associated hyponatremia with heat exhaustion among summertime hikers in Grand Canyon National Park. Cases were selected from among hikers who requested medical help from the National Park Service Emergency Medical Service (EMS) or who presented to the medical clinic on the rim of the canyon with complaints related to exercise in the heat. Of 44 patients who had serum samples analyzed, 7 had hyponatremia with clinically significant symptoms and serum sodium levels <130 mmol/L: 3 had grand mal seizures, 2 had other major central nervous system disorders, and 2 had minor neurological symptoms. Seizures and change of mental status distinguished hyponatremia, (P = 0.0002). Indirect evidence suggests that hyponatremic patients were hyperhydrated. Other common symptoms included nausea, vomiting, headache, and dizziness, but these symptoms did not predict the level of serum sodium. When exercise in the heat is prolonged, hyponatremia is suggested either by altered mental status or by seizures without hyperpyrexia or hypoglycemia. No mortality or long-term morbidity occurred in any of these cases of hyponatremia.     

Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy

OBJECTIVE: To study efficacy and safety of hypertonic saline administration in the management of hyponatremic seizures. DESIGN: Retrospective, observational, cross-sectional study with factorial design. SETTING: In-patient population in a university hospital. PATIENTS: All children admitted with serum sodium concentrations less than 125 mmol/L. Sixty-nine episodes of severe hyponatremia in 60 children were reviewed. Forty-one of these children presented with seizures. INTERVENTIONS: Twenty-five of 41 seizure patients received an iv bolus of 4 to 6 mL/kg body weight of 3% saline. Twenty-eight patients were treated with a benzodiazepine and/or phenobarbital with or without the subsequent administration of hypertonic saline. MEASUREMENTS AND MAIN RESULTS: Thirteen treatment failures and ten instances of apnea occurred among the 28 patients treated with benzodiazepine/phenobarbital. Administration of hypertonic saline resulted in resolution of seizures and apnea in all cases. Those patients receiving 3% saline had a higher serum sodium increase rate from 0 to 4 hrs than the remaining patients (3.1 +/- 1.3 vs. 1.7 +/- 1.2 mmol/L.hr, p less than .01). None developed subsequent neurologic deterioration or clinical manifestations of osmotic demyelination syndrome. CONCLUSION: Treatment of hyponatremic seizures with routine anticonvulsants may be ineffective and is associated with a considerable incidence of apnea. A rapid increase in the serum sodium concentration by 3 to 5 mmol/L with the use of hypertonic saline is safe and efficacious in managing acute symptomatic hyponatremia.     

Exercise-associated hyponatremia in marathon runners: a two-year experience

This study was conducted to better define the pathophysiology, risk factors, and therapeutic approach to exercise-associated hyponatremia. Medical records from all participants in the 1998 Suzuki Rock 'N' Roll Marathon who presented to 14 Emergency Departments (EDs) were retrospectively reviewed to identify risk factors for the development of hyponatremia. Hyponatremic patients were compared to other runners with regard to race time and to other marathon participants seen in the ED with regard to gender, clinical signs of dehydration, and use of nonsteroidal anti-inflammatory drugs (NSAIDs). An original treatment algorithm incorporating the early use of hypertonic saline (HTS) was evaluated prospectively in our own ED for participants in the 1999 marathon to evaluate improvements in sodium correction rate and incidence of complications. A total of 26 patients from the 1998 and 1999 marathons were hyponatremic [serum sodium (SNa) < or =135 mEq/L] including 15 with severe hyponatremia (SNa < or = 125 mEq/L). Three developed seizures and required intubation and admission to an intensive care unit. Hyponatremic patients were more likely to be female, use NSAIDS, and have slower finishing times. Hyponatremic runners reported drinking "as much as possible" during and after the race and were less likely to have clinical signs of dehydration. An inverse relationship between initial SNa and time of presentation was observed, with late presentation predicting lower SNa values. The use of HTS in selected 1999 patients resulted in faster SNa correction times and fewer complications than observed for 1998 patients. It is concluded that the development of exercise-associated hyponatremia is associated with excessive fluid consumption during and after extreme athletic events. Additional risk factors include female gender, slower race times, and NSAID use. The use of HTS in selected patients seems to be safe and efficacious.     

新生儿低钠血症48例病因及治疗分析

目的 探讨新生儿低钠血症的常见病因及治疗原则.方法 回顾性分析我院新生儿科2006年6月至2010年1月收治的48例低钠血症新生儿的临床资料.结果 反应低下(37.5％,18/48)、纳差(31.3％,15/48)是低钠血症的主要表现.常见原因分别有围产期缺氧性疾病、喂养不当、疾病影响、早产因素等.经积极对因处理后,除1例早产儿因严重呼吸窘迫综合征死亡外,余47例3d内血清钠恢复正常.结论 新生儿低钠血症无特异性表现.病因复杂,需区分病因治疗.临床应重视喂养等病史的询问和基础疾病的治疗,早期监测血清钠浓度,及时纠正,以提高治疗成功率,减少后遗症发生.     

Pontine myelinolysis after correction of hyponatremia during burn resuscitation

Central pontine myelinolysis is a neurologic disease produced by the rapid correction of hyponatremia. This report describes the occurrence of central pontine myelinolysis in a patient with burns. The natural history of this paralyzing condition and suggestions for its prevention are discussed. Severely burned and hyponatremic patients are at risk for this disorder because a large amount of sodium ion is typically required for the treatment of burn shock. Awareness of this phenomenon and avoidance of rapid correction of hyponatremia are essential to its prevention.     

Hyponatremia in patients undergoing CAPD: role of water gain and/or malnutrition.

BACKGROUND: Hyponatremia has a number of different causes; some may have serious untoward implications for patients undergoing chronic ambulatory peritoneal dialysis (CAPD). OBJECTIVE: To determine the pathophysiology of hyponatremia in patients on CAPD. METHODS: A retrospective analysis was carried out on 210 patients on CAPD. We selected patients with 2-4 consecutive periods when the plasma sodium concentration was < or =130 mmol/L and again when it was > 133 mmol/L. Exclusion criteria included hyperglycemia, orthostatic hypotension, edema, and inadequate records. RESULTS: An electrolyte-free water gain appeared to be the main cause of hyponatremia in only 1 of 5 patients because this was the only patient with a significant increase in body weight. In 1 patient, there was weight loss in the hyponatremic period, suggesting tissue catabolism was present. In 3 patients, there was neither weight gain nor evidence for a contracted extracellular fluid volume in the hyponatremic period, suggesting that intracellular potassium and phosphate loss could be the major mechanism for their hyponatremia. CONCLUSION: When hyponatremia is due to a catabolic state, its management should aim to restore intracellular fluid composition (i.e., to correct malnutrition).     

Uric acid homeostasis in the evaluation of diuretic-induced hyponatremia.

BACKGROUND: Diuretics are one of the most common causes of severe hyponatremia. The responsible pathogenetic mechanisms remain unclear. Serum uric acid concentration has been proposed as an index of differentiating between two pathophysiologic constructs of diuretic-induced hyponatremia-extracellular volume depletion and syndrome of inappropriate antidiuretic hormone secretion (SIADH)-like state-but its discriminating value has not been verified in large series of patients. Here we attempt to illuminate the pathophysiology of diuretic-induced hyponatremia by focusing on uric acid homeostasis. Additionally, we analyze the epidemiology and clinical characteristics of the disorder. METHODS: We studied prospectively 158 adult patients with hyponatremia on admission to our internal medicine clinic. Here we report on those with diuretic-induced hyponatremia. RESULTS: Forty patients (13 male and 27 female) had diuretic-induced hyponatremia, rendering it the most common cause of the disorder (25.3%). These patients had lower mean ([Na+]) (121.2 +/- 7.2 vs 126.4 +/- 4.1 mEq/L, p = .0001) than the remaining hyponatremic patients. Patients with serum uric acid levels < 4 mg/dL (n = 14) exhibited a biochemical profile consistent with a SIADH-like state, whereas patients with serum uric acid levels > or = 4 mg/d (n = 26) were consistent with extracellular volume depletion. CONCLUSIONS: Diuretics are the most common cause of community-developed hyponatremia. The serum uric acid level effectively discriminates between two biochemical profiles of diuretic-induced hyponatremia, one consistent with extracellular volume depletion and another that simulates SIADH.     

Hyponatremia in the emergency department

Hyponatremia is a clinical manifestation of a wide variety of diseases, some of which have high mortality rates. To assess the prevalence, cause, and prognosis of hyponatremia encountered in the emergency department, we conducted a prospective study at a major hospital in southern Taiwan. We included all adult internal medicine patients treated in the emergency department during a 2-month period. Hyponatremia was defined as a serum sodium level below 134 mEq/L, and cases patients were followed till being discharged. Among the 3,784 patients included, 166 case patients were identified. Most (65%) case patients were hypovolemic, and the overall mortality rate was 17.9%. The mortality rate increased as the sodium level decreased, but was not related to gender, age, cause, or serum potassium level. When 21 hyperglycemic patients whose serum sodium levels went beyond 134 mEq/L after the adjustment for blood sugar levels were excluded, the prevalence of true hyponatremia was 3.83%. The most common underlying diseases were those of the gastrointestinal system. It is concluded that hyponatremia is a common condition encountered in the emergency department. The mortality is correlated with the serum sodium level, and adjustment of the level is required in hyperglycemic patients to make a correct diagnosis. Unlike the cases in some other clinical settings, almost all cases of hyponatremia encountered in the emergency department were not iatrogenic and had recognizable underlying diseases. Therefore, more effort is generally required to identify the cause of hyponatremia cases in the emergency department.     

Biochemical and etiological characteristics of acute hyponatremia in the emergency department

Hyponatremia can be classified as acute or chronic depending on its duration, and treatment options are tailored to this classification. However, it is sometimes difficult to differentiate acute from chronic hyponatremia in the Emergency Department (ED). The objective of this study was to identify characteristics to help diagnose and manage acute hyponatremia in the ED. Patients with acute hyponatremia in the ED were enrolled from a retrospective 2-year chart review. Eleven patients (0.8%) were identified with acute hyponatremia out of a total of 1321 hyponatremic patients. There were nine women and two men. The mean age was 48.9 years. The mean sodium (Na⁺) level was 115 ± 4 mmol/L. Accompanying biochemical abnormalities included hypouricemia and hypouremia with increased fractional excretions of uric acid (UA) and urea. The estimated amount of water intake ranged from 2.5 to 10 liters (mean, 5.1 ± 2.3 liters) during the day before ED presentation. All patients were treated with hypertonic saline and furosemide at a correction rate of 1.6 ± 0.5 mmol/L/h. No patients had neurological sequelae after treatment. The causes of acute hyponatremia included induction of abortion with oxytocin (n = 1), primary polydipsia on neuroleptic agents (n = 2), polyethylene glycol (PEG) preparation for colonoscopy (n = 1), diuretic therapy for hypertension (n = 4), ecstasy use (n = 1), and weight-reducing herbal teas (n = 2). We conclude that in the right clinical setting, high free water intake and low serum urea and UA favor acute hyponatremia. A detailed drug history may be helpful in the differential diagnosis of acute hyponatremia.     

Management of hyponatremia

Hyponatremia is an important electrolyte abnormality with the potential for significant morbidity and mortality. Common causes include medications and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Hyponatremia can be classified according to the volume status of the patient as hypovolemic, hypervolemic, or euvolemic. Hypervolemic hyponatremia may be caused by congestive heart failure, liver cirrhosis, and renal disease. Differentiating between euvolemia and hypovolemia can be clinically difficult, but a useful investigative aid is measurement of plasma osmolality. Hyponatremia with a high plasma osmolality is caused by hyperglycemia, while a normal plasma osmolality indicates pseudohyponatremia or the post-transurethral prostatic resection syndrome. The urinary sodium concentration helps in diagnosing patients with low plasma osmolality. High urinary sodium concentration in the presence of low plasma osmolality can be caused by renal disorders, endocrine deficiencies, reset osmostat syndrome, SIADH, and medications. Low urinary sodium concentration is caused by severe burns, gastrointestinal losses, and acute water overload. Management includes instituting immediate treatment in patients with acute severe hyponatremia because of the risk of cerebral edema and hyponatremic encephalopathy. In patients with chronic hyponatremia, fluid restriction is the mainstay of treatment, with demeclocycline therapy reserved for use in persistent cases. Rapid correction should be avoided to reduce the risk of central pontine myelinolysis. Loop diuretics are useful in managing edematous hyponatremic states and chronic SIADH. In all instances, identifying the cause of hyponatremia remains an integral part of the treatment plan.     

Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis.

Osmotic injury induced by rapid correction of severe chronic hyponatremia has been implicated in the development of central pontine myelinolysis. Organic osmolytes known previously as "idiogenic osmoles" accumulate intracellularly to protect cells from osmotic injury. We investigated the changes of these organic osmolytes as well as electrolytes in the brain during the induction and correction of chronic hyponatremia. Using 1H-nuclear magnetic resonance spectroscopy and HPLC, we found that in rats with chronic hyponatremia (3 d, serum sodium = 109 +/- 3 meq/liter), brain concentrations of myoinositol (41%), glycerophosphorylcholine (45%), phosphocreatine/creatine (60%), glutamate (53%), glutamine (45%), and taurine (37%) were all significantly decreased compared with control values (percentage control value shown, all P less than 0.01). The contribution of measured organic osmolytes and electrolytes to the total brain osmolality change was 23 and 72%, respectively. With rapid correction by 5% NaCl infusion, significant brain dehydration and elevation of brain Na and Cl levels above the normal range occurred at 24 h. These changes were not seen with slow correction by water deprivation. Reaccumulation of most organic osmolytes except glycerophosphorylcholine is delayed during the correction of hyponatremia and is independent of the correction rate of serum sodium. It is concluded that: most of the change of brain osmolality in chronic hyponatremia can be accounted by the changes in organic osmolytes and brain electrolytes; and rapid correction of hyponatremia is associated with an overshoot of brain sodium and chloride levels along with a low organic osmolyte level. The high cerebral ion concentrations in the absence of adequate concentrations of organic osmolytes may be relevant to the development of central pontine myelinolysis.     

Evaluation of the relationship between linezolid exposure and hyponatremia

IntroductionAims of this study were (a) to assess the development ratio of hyponatremia during treatment with linezolid and (b) to evaluate the relationship between the risk of hyponatremia and linezolid exposure and patient background.MethodClinical data including linezolid serum concentrations and serum sodium values were collected at Toyama University Hospital and Kyorin University Hospital. Data from 89 patients were used for the analysis, and a nadir serum sodium level ≤130 mmol/L during the treatment with linezolid was defined as hyponatremia. Mann-Whitney's U test was used to evaluate the effects of the area under the time-concentration curve (AUC) of linezolid at the nadir sodium level, clinical characteristics (e.g. laboratory data), and baseline serum sodium levels on the development of hyponatremia.ResultsThe hyponatremia was occurred in 21 of 89 patients (23.6%). Data are compared for baseline and nadir serum sodium levels of patients with and without hyponatremia. In both groups, nadir serum sodium levels were significantly different from those of the baseline values (P < 0.05). The values of AUC_0-12, accumulated AUC, baseline serum sodium levels and age were significantly different between patients with and without hyponatremia (P < 0.05).ConclusionsLinezolid exposure, age, and baseline sodium levels were detected as the risk factors for linezolid-related hyponatremia. Our findings suggest that regular monitoring of serum sodium levels is desirable during treatment with linezolid, especially for the elderly and patients with low serum sodium levels before the start of linezolid administration.     

EVEREST study: Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan

Acute heart failure syndromes are a common cause of emergency department visits and hospitalization in North America and Europe. Although in-hospital mortality is relatively low, the postdischarge mortality and rehospitalization rates can be as high as 10–15 and 30%, respectively, within 60–90 days following discharge. It appears that the main reason for admission and readmission for heart failure is related to congestion manifested by dyspnea, jugular venous distension and edema. Often, congestion is associated with dilutional hyponatremia that is difficult to treat. Hyponatremia is an important predictor of increased mortality and the available therapies to treat congestion and/or hyponatremia are often ineffective and/or unsafe. Accordingly, there is an unmet need to develop a new agent that effectively relieves congestion due to high filling pressure without worsening renal function and improving or normalizing serum sodium in hyponatremic patients. This paper provides an overview of a new compound, tolvaptan, an oral selective V₂-vasopressin antagonist in light of the recently published Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. The biochemical and pharmacological properties are discussed in conjunction with its clinical efficacy and safety, exploring the potential role of tolvaptan in the management of acute heart failure syndromes presenting with or without hyponatremia.